The unambiguous demonstration of opioid receptor types, and their endogenous ligands, the endorphins, together with a diverse range of synthetic ligands, has created exciting opportunities for research highly relevant to drug abuse. A major objective of this project is to continue the process of defining new opioid receptor subtypes. This process is optimally accomplished by synergistic collaborations with medicinal chemists to develop (a) selective high affinity ligands for each subtype (b) irreversible ligands with receptor subtype specificity and (c) enantiomeric pairs of these ligands for detection of receptor mediated effects. delta receptor antagonists attenuate alcohol consumption and block morphine tolerance and dependence. The CPS is a leading lab in the determination of delta receptor subtypes.: recent studies demonstrated two subtypes of the delta-ncx binding site, and provided new information about subtypes of the delta-cx subtype. The determination of delta receptor subtypes may lead to new medicines for the treatment of alcoholism and drug addiction. Converging lines of investigation suggest that kappa receptor antagonists may be useful for the treatment of depression, anxiety, psychosis and craving. Studies reported last year demonstrated up to four subtypes of kappa opioid receptors in rat, guinea pig and human brain, suggesting that it may be possible to develop kappa agonists devoid of psychotomimetic side effects. More recent studies have resolved yet more kappa receptor subtypes. Investigations carried out with highly potent analogs of (+)- cis-3-methylfentanyl have identified analogs over 100,000 x the antinociceptive potency of morphine and allowed us to determine the stereochemical requirements of pseudoirreversible inhibition. These drugs provide unique information about the topography of the mu receptor binding site, and interact with the mu receptor according to a pseudoallosteric mechanism. The notion that dysfunction of the CNS opioid receptor/endorphin system underlies certain mental illnesses, and contributes to drug abuse, remains a viable, but unproved, hypotheses. Recent work conducted in collaboration with researchers of the Liver Disease Section, NIDDK, provided strong evidence that the opioid receptor/endorphin system plays an important role in the pathogenesis of choleostatic liver disease. These data will provide a useful model system for studying the more complex phenomena associated with substance abuse.